Nitric oxide (NO), a small molecule which is highly toxic at moderate concentrations, is a key messenger in mammalian physiology. NO is produced in humans by three related enzymes which comprise the nitric oxide synthase (NOS) family.
Endothelial NOS (ENOS) produces NO which controls vascular tone (hence blood pressure), dilates the airways, and controls numerous processes dependent on local dilation of blood vessels (such as gas exchange in lungs, penile erection, and renal function). Brain or neuronal NOS (BNOS or NNOS) produces NO which functions as a neurotransmitter. It controls peristalsis in the gut, and is implicated in neural potentiation and brain development. NNOS and ENOS are constitutive enzymes controlled by intracellular calcium and the regulatory protein calmodulin (CAM). When the level of calcium in the cell rises, NNOS and ENOS bind calmodulin and are turned on to start NO production.
A third, inducible NOS, immune NOS or macrophage NOS (INOS or MNOS), is synthesized by the immune system in response to an immune challenge. Upon induced expression, this enzyme is always active; it has a calmodulin binding site, but binds calmodulin tightly even at low calcium levels. INOS produces orders of magnitude more NO than other NO synthases. This NO level is cytotoxic to tumor cells, bacteria, and other pathogenic organisms.
While INOS thus appears to be an important component of immune response, its activity is highly toxic as well. Excess production of NO by INOS can be responsible for toxic shock syndrome, septic shock, and killing of islet cells in diabetes. Excess NO production by INOS has also been implicated in a wide range of other autoimmune conditions, including arthritis and other inflammatory conditions.
Thus, it is of critical importance to learn to control NO synthesis by one NOS, without interfering with the activity of other NO synthases. Currently, inhibitors of INOS also inhibit NNOS and ENOS.